The characterization of an intestine-like genomic signature maintained during Barrett's-associated adenocarcinogenesis reveals an NR5A2-mediated promotion of cancer cell survival.
Sci Rep, 2016/09/02;6:32638.
Duggan SP[1, 2], Behan FM[3], Kirca M[4], Zaheer A[4], McGarrigle SA[5], Reynolds JV[5], Vaz GM[6], Senge MO[6], Kelleher D[1, 2]
Affiliations
PMID: 27586588DOI: 10.1038/srep32638
Impact factor: 4.996
Abstract
Barrett's oesophagus (BO), an intestinal-type metaplasia (IM), typically arising in conjunction with gastro-oesophageal reflux disease, is a prominent risk factor for the development of oesophageal adenocarcinoma (OAC). The molecular similarities between IM and normal intestinal tissues are ill-defined. Consequently, the contribution of intestine-enriched factors expressed within BO to oncogenesis is unclear. Herein, using transcriptomics we define the intestine-enriched genes expressed in meta-profiles of BO and OAC. Interestingly, 77% of the genes differentially expressed in a meta-profile of BO were similarly expressed in intestinal tissues. Furthermore, 85% of this intestine-like signature was maintained upon transition to OAC. Gene networking analysis of transcription factors within this signature revealed a network centred upon NR5A2, GATA6 and FOXA2, whose over-expression was determined in a cohort of BO and OAC patients. Simulated acid reflux was observed to induce the expression of both NR5A2 and GATA6. Using siRNA-mediated silencing and an NR5A2 antagonist we demonstrate that NR5A2-mediated cancer cell survival is facilitated through augmentation of GATA6 and anti-apoptotic factor BCL-XL levels. Abrogation of NR5A2-GATA6 expression in conjunction with BCL-XL co-silencing resulted in synergistically increased sensitivity to chemotherapeutics and photo-dynamic therapeutics. These findings characterize the intestine-like signature associated with IM which may have important consequences to adenocarcinogenesis.
MeSH terms
Adenocarcinoma; Apoptosis; Barrett Esophagus; Cell Line, Tumor; Cell Survival; Esophageal Neoplasms; GATA6 Transcription Factor; Gastric Acid; Gastroesophageal Reflux; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Gene Silencing; Genome, Human; Humans; Intestinal Mucosa; Receptors, Cytoplasmic and Nuclear; Reproducibility of Results; bcl-X Protein
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